Male reproductive function is regulated by a classical endocrine feedback system involving (1) the production of gonadotropin-releasing hormone (GnRH) in a pulsatile manner from the hypothalamus, (2) the release of gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary in response to GnRH, (3) the LH-induced synthesis of testosterone (T) from testicular Leydig cells, and (4) the negative feedback of T on GnRH and LH/FSH secretion. Surprisingly, studies on a mouse null mutant for the mononuclear phagocytic growth factor, colony stimulating factor-1 (CSF-1), showed a profound disruption of this hypothalamic-pituitary-gonadal axis. CSF-1 Nullizygous mice, when compared to wild type mice have ten-fold lower circulating T concentrations due to reduced testicular biosynthesis and ten-fold lower serum LH concentrations. The reduced T concentrations result in low libido and a decreased number of epididymal sperm. Furthermore, the hypothalamic- pituitary feedback loop to T is lost in these mice. The steroidogenic function of csfm/op Leydig cells can be restored by LH and, in turn, LH release can be induced in vivo by a GnRH agonist. These data suggest a role for CSF-1 in the establishment and/or regulation of the hypothalamic-pituitary-gonadal axis. Since the only identified CSF-1 receptor-bearing cells in males are members of the mononuclear phagocytic lineage, it is probably that CSF-1 exerts its effects through macrophages. Endocrine restoration will indicate whether the primary defect in csfm/op/csfm/op mice is in the hypothalamus or whether the hypothalamic defect is a secondary consequence of T-deprivation at critical times during development. Detailed analysis of the hypothalamus and pituitary of csfm/op/csfm/op male mice in temporally and spatially restricted patterns. This, coupled with determination of CSF-1 expressing and responding cells will establish a causal relationship between CSF-1 action and the development of the hypothalamic-pituitary-gonadal axis. Studies in the csfm/op/sfm/op mouse should define precisely, a unique and novel role for CSF-1 in this classical endocrine feedback system and the involvement of the important immune cells, macrophages, in these processes. This should significantly enhance our understanding of some aspects of human infertility and will provide important insight into the mechanism by which infection can affect fertility in healthy human males.